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1.
Clin Transl Med ; 14(6): e1734, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38888967

ABSTRACT

BACKGROUND: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood. METHODS: Surgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single-cell RNA-sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single-cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations. RESULTS: There was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone-lysine N-methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto-oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. CONCLUSIONS: We revealed the previously underappreciated involvement of the KMT2A‒STAT3/GATA3‒CCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti-inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications. HIGHLIGHTS: Single-cell RNA-sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands. PA cells show a pervasive increase in gene expression linked to KMT2A upregulation. KMT2A-mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2. PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis.


Subject(s)
Adenoma , Histone-Lysine N-Methyltransferase , Inflammation , Parathyroid Neoplasms , Humans , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , Adenoma/genetics , Adenoma/metabolism , Adenoma/pathology , Inflammation/genetics , Inflammation/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Proto-Oncogene Mas , Cell Proliferation/genetics
2.
Endocrinol Metab (Seoul) ; 39(2): 375-386, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38509667

ABSTRACT

BACKGRUOUND: Parathyroid adenoma (PA) is a common endocrine disease linked to multiple complications, but the pathophysiology of the disease remains incompletely understood. The study aimed to identify the key regulator proteins and pathways of PA according to functionality and volume through quantitative proteomic analyses. METHODS: We conducted a retrospective study of 15 formalin-fixed, paraffin-embedded PA samples from tertiary hospitals in South Korea. Proteins were extracted, digested, and the resulting peptides were analyzed using liquid chromatography-tandem mass spectrometry. Pearson correlation analysis was employed to identify proteins significantly correlated with clinical variables. Canonical pathways and transcription factors were analyzed using Ingenuity Pathway Analysis. RESULTS: The median age of the participants was 52 years, and 60.0% were female. Among the 8,153 protein groups analyzed, 496 showed significant positive correlations with adenoma volume, while 431 proteins were significantly correlated with parathyroid hormone (PTH) levels. The proteins SLC12A9, LGALS3, and CARM1 were positively correlated with adenoma volume, while HSP90AB2P, HLA-DRA, and SCD5 showed negative correlations. DCPS, IRF2BPL, and FAM98A were the main proteins that exhibited positive correlations with PTH levels, and SLITRK4, LAP3, and AP4E1 had negative correlations. Canonical pathway analysis demonstrated that the RAN and sirtuin signaling pathways were positively correlated with both PTH levels and adenoma volume, while epithelial adherence junction pathways had negative correlations. CONCLUSION: Our study identified pivotal proteins and pathways associated with PA, offering potential therapeutic targets. These findings accentuate the importance of proteomics in understanding disease pathophysiology and the need for further research.


Subject(s)
Adenoma , Blood Proteins , Galectins , Parathyroid Neoplasms , Proteomics , Humans , Parathyroid Neoplasms/pathology , Parathyroid Neoplasms/metabolism , Female , Middle Aged , Male , Retrospective Studies , Adenoma/pathology , Adenoma/metabolism , Adult , Proteomics/methods , Tumor Burden , Aged , Republic of Korea , Biomarkers, Tumor/metabolism , Parathyroid Hormone/blood
3.
Endocrine ; 84(3): 1146-1153, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38340242

ABSTRACT

PURPOSE: Parathyroid carcinoma (PC) is an endocrine malignancy with a poor prognosis. However, the diagnosis of PC is still a difficult problem. A model with immunohistochemical (IHC) staining of 5 biomarkers has been reported from limited samples for the differential diagnosis of PC. In the present study, a series of IHC markers was applied in relatively large samples to optimize the diagnostic model for PC. METHODS: In this study, 44 patients with PC, 6 patients with atypical parathyroid tumors and 57 patients with parathyroid adenomas were included. IHC staining for parafibromin, Ki-67, galectin-3, protein-encoding gene product 9.5 (PGP9.5), E-cadherin, and enhancer of zeste homolog 2 (EZH2) was performed on formalin-fixed, paraffin-embedded tissue samples. The effects of clinical characteristics, surgical procedure, and IHC staining results of tumor tissues on the diagnosis and prognosis of PC were evaluated retrospectively. RESULTS: A logistic regression model with IHC results of parafibromin, Ki-67, and E-cadherin was created to differentiate PC with an area under the curve of 0.843. Cox proportional hazards analysis showed that negative parafibromin staining (hazard ratio: 3.26, 95% confidence interval: 1.28-8.34, P = 0.013) was related to the recurrence of PC. CONCLUSION: An IHC panel of parafibromin, Ki-67 and E-cadherin may help to distinguish PC from parathyroid neoplasms. Among the 6 IHC markers and clinical features examined, the risk factor related to PC recurrence was parafibromin staining loss.


Subject(s)
Biomarkers, Tumor , Cadherins , Immunohistochemistry , Parathyroid Neoplasms , Humans , Parathyroid Neoplasms/diagnosis , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , Male , Female , Middle Aged , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/analysis , Adult , Aged , Cadherins/metabolism , Cadherins/analysis , Retrospective Studies , Ki-67 Antigen/metabolism , Ki-67 Antigen/analysis , Diagnosis, Differential , Carcinoma/diagnosis , Carcinoma/metabolism , Carcinoma/pathology , Prognosis , Tumor Suppressor Proteins/analysis , Tumor Suppressor Proteins/metabolism , Galectin 3/metabolism , Galectin 3/analysis , Adenoma/diagnosis , Adenoma/metabolism , Adenoma/pathology
4.
Stem Cell Res ; 75: 103311, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38237426

ABSTRACT

CDC73-related disorders are inherited in an autosomal dominant manner. An individual with a CDC73-related disorder may have inherited the disorder from an affected parent or developed it as the result of a de novo pathogenic variant of CDC73. The iPSC line was obtained by reprogramming the PBMCs of a patient with a heterozygous type mutation of the CDC73 gene. This cell line could be useful to scrutinize and study the development of CDC73-associated parathyroid carcinoma.


Subject(s)
Induced Pluripotent Stem Cells , Parathyroid Neoplasms , Humans , Induced Pluripotent Stem Cells/metabolism , Tumor Suppressor Proteins/genetics , Mutation/genetics , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , Transcription Factors/genetics
5.
Eur J Endocrinol ; 188(4): 385-394, 2023 Apr 05.
Article in English | MEDLINE | ID: mdl-36995894

ABSTRACT

OBJECTIVE: Diagnosing parathyroid carcinoma (PC) is complicated and controversial that early diagnosis and intervention are often difficult. Therefore, we aimed to elucidate the protein signatures of PC through quantitative proteomic analyses to aid in the early and accurate diagnosis of PC. DESIGN: We conducted a retrospective cohort study. METHODS: We performed liquid chromatography with tandem mass spectrometry using formalin-fixed paraffin-embedded samples. For the analyses, 23 PC and 15 parathyroid adenoma (PA) tissues were collected from 6 tertiary hospitals in South Korea. RESULTS: The mean age of the patients was 52 years, and 63% were women. Proteomic expression profiling revealed 304 differentially expressed proteins (DEPs) with a cut-off of P < .05 and fold change >1.5. Among DEPs, we identified a set of 5 proteins that can discriminate PC from PA: carbonic anhydrase 4 (CA4), alpha/beta hydrolase domain-containing protein 14B (ABHD14B), laminin subunit beta-2 (LAMB2), CD44 antigen (CD44), and alpha-1-acid glycoprotein 1 (ORM1) that exhibited the highest area under the curve of 0.991 in neural network model. The nuclear percentage of CA4 and LAMB2 in immunohistochemistry was significantly lower in PC tissue than in the PA (CA4: 2.77 ± 1.96%, 26.2 ± 3.45%, P < .001; LAMB2: 6.86 ± 3.46%, 38.54 ± 4.13%, P < .001). The most enriched canonical pathways in PC included glycoprotein-6 signaling and mammalian target of rapamycin (mTOR). CONCLUSIONS: We identified key proteins differentially expressed between PC and PA using proteomic analyses of parathyroid neoplasms. These findings may help to diagnose PC accurately and elucidate potential therapeutic targets.


Subject(s)
Parathyroid Neoplasms , Humans , Female , Middle Aged , Male , Parathyroid Neoplasms/metabolism , Retrospective Studies , Proteomics , Republic of Korea
6.
Mol Cell Biochem ; 478(10): 2351-2359, 2023 Oct.
Article in English | MEDLINE | ID: mdl-36703095

ABSTRACT

Primary hyperparathyroidism is a common endocrine disorder. Interestingly, the majority (75%) of parathyroid tumors are localized to the inferior parathyroid glands. To date, the reason for this natural bias has not been investigated. We assessed the global gene expression profile of superior and inferior glands obtained from forensic autopsies. The genes with significant differential expression between superior and inferior parathyroids were further assessed by RT-PCR in 19 pairs. As an iterative approach, additional genes with an established role in parathyroid disorders, i.e., CASR, MAFB, PAX9, TBCE, TBX1, VDR, MEN1, CCND1, and CDC73 were also evaluated by RT-PCR in all 19 pairs of superior and inferior parathyroid glands. Seven homeobox genes, namely HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, and one encoding for ALDH1A2 showed a lower expression in the inferior parathyroid glands than in the superior. Conversely, SLC6A1 showed a higher expression in the inferior glands. Of the nine genes with significant differential mRNA expression among superior and inferior glands HOXB9, HOXB4 and IRX1 could be detected by western blotting/mass spectrometry. The study is the first to show the differential expression of nine genes HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, ALDH1A2, and SLC6A1 in inferior versus the superior parathyroid glands. This could have potential implications for the preferential localization of parathyroid tumors to the inferior parathyroid glands as observed in patients with primary hyperparathyroidism.


Subject(s)
Hyperparathyroidism, Primary , Parathyroid Neoplasms , Humans , Parathyroid Glands/chemistry , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , Hyperparathyroidism, Primary/metabolism , Hyperparathyroidism, Primary/pathology , Blotting, Western , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism
7.
J Transl Med ; 20(1): 368, 2022 08 16.
Article in English | MEDLINE | ID: mdl-35974370

ABSTRACT

Primary hyperparathyroidism (PHPT) is mainly caused by parathyroid adenoma, which produces excess parathyroid hormones. Its pathogenic mechanisms have not yet been fully understood. To investigate the mechanism in the pathogenesis of PHPT, the transcriptome and genome-wide DNA methylation profiles of parathyroid adenoma were analyzed. The candidate genes that may be involved in the PHPT were verified via qRT-PCR, immunohistochemistry, western blot, and methylation-specific PCR. A total of 1650 differentially expressed genes and 2373 differentially methylated regions were identified. After the integration of its transcriptome and DNA methylation data, IL6, SYP, GNA01, and pro-opiomelanocortin (POMC) were the candidate genes that demonstrated a similar pattern between their mRNA expression and DNA methylation status. Of the 4 candidate genes, POMC, a pro-peptide which is processed to a range of bioactive peptide products like ACTH, was further confirmed to be expressed at low levels at both the mRNA and protein levels, which may be due to POMC promoter hypermethylation. Hypermethylation of the POMC promoter may contribute to its low expression, which may be involved in the pathogenesis of PHPT.


Subject(s)
DNA Methylation , Parathyroid Neoplasms , Pro-Opiomelanocortin , Gene Expression , Humans , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism , Pro-Opiomelanocortin/genetics , Pro-Opiomelanocortin/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
8.
Vitam Horm ; 120: 289-304, 2022.
Article in English | MEDLINE | ID: mdl-35953114

ABSTRACT

A parathyroid adenoma comprises 80-85% as a cause of primary hyperparathyroidism. The clonal origin of most parathyroid adenomas suggests a defect at the level of the gene controlling growth of the parathyroid cell or the expression of parathyroid hormone (PTH). Two genes, MEN1 and CCND1, a tumor suppressor and a proto-oncogene respectively, have been solidly established as primary tumorigenic drivers in parathyroid adenomas. As well, germline and somatic mutation of other genes involved in cell cycle regulation or PTH regulation have been discovered in parathyroid adenomas. Moreover, comparative genomic studies between parathyroid adenomas and normal parathyroid tissues have suggested more complex genetic landscape. Microarray analysis have revealed differential expression profiles of genes involved in cell cycle regulation, growth factors, apoptotic pathway, or PTH synthesis or regulation pathway such as CASR, GCM2 and KL (Klotho). Furthermore, recent next-generation sequencing analysis reconfirmed previous finding or revealed novel finding, suggesting signal peptidase complex subunit (SPCS2), ribosomal proteins (RPL23, RPL26, RPN1, RPS25), the endoplasmic reticulum membrane (SEC11C, SEC11A, SEC61G), Klotho, cyclin D1, ß-catenin, VDR, CaSR and GCM2 may be important factors contributing to the parathyroid adenoma.


Subject(s)
Adenoma , Parathyroid Neoplasms , Adenoma/genetics , Adenoma/metabolism , Adenoma/pathology , Humans , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Hormone/genetics , Parathyroid Hormone/metabolism , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , Peptide Hydrolases/genetics , Peptide Hydrolases/metabolism , SEC Translocation Channels/genetics , SEC Translocation Channels/metabolism , Transcriptome
9.
Eur J Endocrinol ; 186(3): 351-366, 2022 Feb 04.
Article in English | MEDLINE | ID: mdl-35038313

ABSTRACT

OBJECTIVE: The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma. DESIGN: We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants. METHODS: Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses. RESULTS: A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter. CONCLUSIONS: We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.


Subject(s)
Hyperparathyroidism/genetics , Hypoparathyroidism/genetics , Mutation , Nuclear Proteins/genetics , Parathyroid Neoplasms/genetics , Transcription Factors/genetics , Adult , Aged , Aged, 80 and over , Animals , Binding Sites , Calcium/blood , Calcium/urine , DNA/blood , DNA/metabolism , Female , Humans , Hyperparathyroidism/metabolism , Hyperparathyroidism/pathology , Hypoparathyroidism/blood , Infant , Male , Mice , Middle Aged , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Parathyroid Glands/pathology , Parathyroid Glands/surgery , Parathyroid Hormone/blood , Parathyroid Hormone/genetics , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , Pedigree , Promoter Regions, Genetic , Sequence Analysis, DNA , Transcription Factors/chemistry , Transcription Factors/metabolism
10.
J Endocrinol Invest ; 45(2): 337-346, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34302683

ABSTRACT

PURPOSE: Calcium sensing receptor (CaSR), on the surface of normal parathyroid cells, is essential for maintaining serum calcium levels. The normal pattern of CaSR immunostaining remains undefined and is presumptively circumferential. Given the physiological variation in serum calcium, we postulated that CaSR expression could not be uniformly circumferential. Also, cytoplasmic expression has not been evaluated either in normal or pathological tissues. We studied normal parathyroid tissues derived from forensic autopsies and those rimming parathyroid adenomas for membranous and cytoplasmic CaSR immunoexpression. Results were compared with primary hyperparathyroidism (PHPT) to look for any pathogenetic implications. MATERIALS AND METHODS: We evaluated 34 normal parathyroid tissues from 11 autopsies, 30 normal rims, 45 parathyroid adenoma, 10 hyperplasia, and 7 carcinoma cases. Membranous expression was categorized complete/incomplete and weak/moderate/strong; scored using Her2/Neu and Histo-scores; predominant pattern noted. Cytoplasmic expression was categorized negative/weak/moderate/strong; predominant intensity noted. RESULTS: Normal autopsy-derived parathyroid tissues were Her2/Neu 3 + , but incomplete membranous staining predominated in 85%. Their immune-scores were significantly more than the cases (p < < 0.05). The mean histo-score of normal rims was intermediate between the two (p < < 0.05). Cytoplasmic expression was strong in all autopsy-derived tissues, weak/negative in hyperplasia (100%), moderate in 16% adenomas, and 43% carcinomas. CONCLUSIONS: Normal autopsy-derived parathyroid tissues showed strong but predominantly incomplete membranous expression. Surface CaSR expression decreased in PHPT and is probably an early event in parathyroid adenoma, seen even in normal rims. Whether there is a defect in CaSR trafficking from the cytoplasm to the cell surface in adenoma and carcinoma needs further evaluation.


Subject(s)
Hyperparathyroidism, Primary , Parathyroid Glands , Parathyroid Neoplasms , Receptors, Calcium-Sensing/analysis , Adult , Autopsy , Female , Gene Expression Profiling/methods , Humans , Hyperparathyroidism, Primary/metabolism , Hyperparathyroidism, Primary/pathology , Immunohistochemistry , Immunologic Techniques/methods , Intracellular Calcium-Sensing Proteins/metabolism , Male , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology
11.
Exp Clin Transplant ; 20(9): 854-862, 2022 09.
Article in English | MEDLINE | ID: mdl-30995898

ABSTRACT

OBJECTIVES: Tissue-specific immunogenicity can be characterized by the determination of human leukocyte antigens (HLA). Parathyroid hyperplasia tissue cells are presumed to have the ability to lose HLA class I expression profile during cultivation, whereas healthy parathyroid cells are presumed to already express HLA class I molecules at low levels. However, there are conflicting results about the expression of HLA class I antigens. In this study, our aim was to evaluate different patterns of HLA class I expression in different parathyroid tissue cells. MATERIALS AND METHODS: Parathyroid tissue cells were isolated enzymatically and cultured in vitro. Expression of HLA class I (HLA-A, HLA-B, HLA-C) mRNA and protein levels were studied in 7 parathyroid adenomas and 9 parathyroid hyperplasia tissue samples by reverse transcriptase-polymerase chain reaction and Western blot analyses. RESULTS: HLA-A protein expression remained stable in parathyroid adenoma and hyperplasia tissue, but HLA-A mRNA expression decreased in adenoma tissue. In parathyroid hyperplasia tissue, HLA-B protein expression remained stable, although mRNA expres-sion levels decreased during cultivation. HLA-C mRNA expression was steady in parathyroid adenoma yet significantly decreased in hyperplasia tissue samples. HLA-C protein expression levels were below 30 pg for both types of parathyroid tissue during cultivation. CONCLUSIONS: HLA class I expression levels of para-thyroid hyperplasia and adenoma tissue were not found to be similar. Parathyroid hyperplasia tissue is the donor tissue for the treatment of permanent hypoparathyroidism. Therefore, expression patterns of HLA class I are directly relevant to the transplant process. In particular, the HLA region is highly polymorphic, and, as a consequence of this, heterogeneous correlations among HLA-A, HLA-B, and HLA-C expression patterns of parathyroid tissue should be evaluated in detail before transplant for future studies.


Subject(s)
Adenoma , Parathyroid Neoplasms , Adenoma/genetics , Adenoma/metabolism , Adenoma/pathology , HLA Antigens/genetics , HLA-C Antigens/metabolism , Humans , Hyperplasia/metabolism , Hyperplasia/pathology , Parathyroid Glands , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Directed DNA Polymerase/metabolism , Treatment Outcome
12.
Rev. cir. (Impr.) ; 73(6): 748-752, dic. 2021. ilus
Article in Spanish | LILACS | ID: biblio-1388891

ABSTRACT

Resumen Introducción: A pesar de que el carcinoma de paratiroides es uno de los cánceres menos frecuentes del mundo, es importante tenerlo en cuenta al plantear el diagnóstico diferencial del hiperparatiroidismo primario, ya que su diagnóstico temprano tiene repercusiones en el tratamiento y el pronóstico vital del paciente. Caso Clínico: A continuación, se expone un caso clínico de un paciente con sintomatología abigarrada de hiperfunción paratiroidea que, dada la sospecha clínica de carcinoma de paratiroides y la no infiltración de estructuras adyacentes, fue tratado con una paratiroidectomía. Conclusión: Esta cirugía supone una menor morbilidad, sin suponer un detrimento para la supervivencia global del paciente.


Introduction: Parathyroid carcinoma should be taken into consideration among the differential diagnosis of primary hyperparathyroidism, even though it is one of the less common malignant tumours in the world, because an early diagnosis is essential for the treatment and the prognosis of the patient. Case Report: We present the case of a patient whose symptoms were compatible with hyperfunction of parathyroid gland. Due to the malignant disease suspicion and the non-invasion of adjacent tissue, he was treated with a parathyroidectomy. Conclusión: This type of treatment supposes a lower morbidity without decrease in overall survival, according to bibliography.


Subject(s)
Humans , Male , Adult , Parathyroid Hormone/metabolism , Parathyroid Neoplasms/metabolism , Lymphatic Metastasis , Parathyroid Neoplasms/pathology , Thyroidectomy , Tomography, X-Ray Computed , Parathyroidectomy , Ultrasonography
13.
Int J Mol Sci ; 22(19)2021 Sep 28.
Article in English | MEDLINE | ID: mdl-34638805

ABSTRACT

Tumors of the parathyroid glands are common endocrine diseases almost always characterized by parathyroid hormone hypersecretion that determines the clinical manifestations of primary hyperparathyroidism, such as fatigue, kidney problems, weakness, brittle bones, and other symptoms. Most parathyroid neoplasia are benign adenomas, although rare malignant forms have been described. They are heterogeneous in terms of clinical presentation and the associated signs and symptoms overlap with those of disease and aging. Furthermore, most patients with hypercalcemia are discovered during routine blood tests for other reasons. Surgical removal is considered the main therapeutic option to cure these endocrine tumors and, therefore, innovative therapeutic approaches are actively required. Recently, a growing number of studies have suggested that alterations to the epigenetic mechanisms could play a pivotal role in parathyroid tumorigenesis. Most of the attention has been focused on non-coding RNAs (ncRNAs) (i.e., miRNAs, lncRNAs, and circRNAs) whose expression profile has been found to be deregulated in parathyroid tumors. The aim of the present paper is to give an insight into the ncRNAs involved in parathyroid tumorigenesis, which could be used in the future either as innovative diagnostic biomarkers or as therapeutic targets for the treatment of this endocrine neoplasia.


Subject(s)
Parathyroid Neoplasms/metabolism , RNA, Untranslated/analysis , Biomarkers, Tumor/analysis , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs , Parathyroid Neoplasms/diagnosis , Parathyroid Neoplasms/genetics , RNA, Circular , RNA, Long Noncoding , RNA, Untranslated/metabolism
14.
J Clin Endocrinol Metab ; 106(11): 3168-3183, 2021 10 21.
Article in English | MEDLINE | ID: mdl-34272844

ABSTRACT

CONTEXT: The biochemical basis for clinical variability in primary hyperparathyroidism (PHPT) is poorly understood. OBJECTIVE: This study aimed to define parathyroid tumor biochemical properties associated with calcium-sensing failure in PHPT patients, and to relate differences in these profiles to variations in clinical presentation. METHODS: Preoperative clinical data from a sequential series of 39 patients undergoing surgery for PHPT at an endocrine surgery referral center in a large, public university hospital were evaluated for correlation to parathyroid tumor biochemical behavior. An intact tissue, ex vivo interrogative assay was employed to evaluate the calcium-sensing capacity of parathyroid adenomas relative to normal donor glands. Tumors were functionally classified based on calcium dose-response curve profiles, and clinical parameters were compared among the respective classes. Changes in the relative expression of 3 key components in the calcium/parathyroid hormone (PTH) signaling axis-CASR, RGS5, and RCAN1-were evaluated as potential mechanisms for calcium-sensing failure. RESULTS: Parathyroid adenomas grouped into 3 distinct functional classes. Tumors with diminished calcium sensitivity were the most common (18 of 39) and were strongly associated with reduced bone mineral density (P = 0.0009). Tumors with no calcium-sensing deficit (11 of 39) were associated with higher preoperative PTH (P = 0.036). A third group (6/39) displayed a nonsigmoid calcium/PTH response curve; 4 of these 6 tumors expressed elevated RCAN1. CONCLUSION: Calcium-sensing capacity varies among parathyroid tumors but downregulation of the calcium-sensing receptor (CASR) is not an obligate underlying mechanism. Differences in tumor calcium responsiveness may contribute to variations in PHPT clinical presentation.


Subject(s)
Adenoma/pathology , Biomarkers/metabolism , DNA-Binding Proteins/metabolism , Hyperparathyroidism, Primary/pathology , Muscle Proteins/metabolism , Parathyroid Neoplasms/pathology , RGS Proteins/metabolism , Receptors, Calcium-Sensing/metabolism , Adenoma/metabolism , Aged , Calcium/metabolism , Case-Control Studies , Female , Follow-Up Studies , Humans , Hyperparathyroidism, Primary/metabolism , Male , Middle Aged , Parathyroid Hormone/metabolism , Parathyroid Neoplasms/metabolism , Prognosis , Signal Transduction
15.
Horm Metab Res ; 53(7): 444-452, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34169499

ABSTRACT

There are multiple imaging modalities in primary hyperparathyroidism. Ultrasound examination and subtraction scintigraphy are usually the first-line imaging techniques. When these results are negative or inconsistent, additional [11C]-methionine PET/CT (MET-PET/CT) or 4-dimensional computed tomography can be performed. ​This study aims to evaluate MET-PET/CT in comparison with other imaging techniques in primary hyperparathyroidism. This is a retrospective cohort study. Eighty-four patients with primary hyperparathyroidism, who underwent parathyroid surgery, were included. ​Imaging results have been correlated to the perioperative drop in parathyroid hormone level and to the pathological analysis. ​Descriptive statistics are used, supplemented with 95% Clopper-Pearson confidence intervals for sensitivity and specificity and a sub-analysis with the McNemar test on paired data only. The per-lesion sensitivity of MET-PET/CT seems higher than that of [99mTc]-sestamibi or [99mTc]-tetrofosmin and [99mTc]-pertechnetate subtraction scintigraphy. The McNemar test, on paired data only, shows significantly higher sensitivity of MET-PET/CT compared to ultrasound (p=0.039) and significantly higher specificity of ultrasound compared to subtraction scintigraphy (p=0.035).​ MET-PET/CT after inconclusive or negative ultrasound and/or subtraction scintigraphy has an additional value in 70% of the cases.​ Preoperative parathyroid hormone levels were higher in patients in whom MET-PET/CT correctly predicted the pathological parathyroid glands, compared to those where MET-PET/CT missed at least one adenoma. The same trend was seen for 4-dimensional computed tomography. In conclusion, MET-PET/CT seems a valuable imaging modality in primary hyperparathyroidism, at least as second line imaging approach, with a higher per-lesion sensitivity than ultrasound in such setting. Especially when ultrasound and/or subtraction scintigraphy are inconclusive or negative, MET-PET/CT directs the surgeon to the correct localization of the parathyroid adenoma.


Subject(s)
Adenoma/diagnosis , Carbon Radioisotopes/analysis , Methionine/metabolism , Parathyroid Neoplasms/diagnosis , Adenoma/diagnostic imaging , Adenoma/metabolism , Female , Follow-Up Studies , Humans , Male , Middle Aged , Parathyroid Neoplasms/diagnostic imaging , Parathyroid Neoplasms/metabolism , Positron Emission Tomography Computed Tomography , Prognosis , Retrospective Studies
16.
Front Endocrinol (Lausanne) ; 12: 631680, 2021.
Article in English | MEDLINE | ID: mdl-34054720

ABSTRACT

Purpose: Hyperparathyroidism is the third most common endocrine disease. Parathyroid adenoma (PA) accounts for approximately 85% of cases of primary hyperparathyroidism, but the molecular mechanism is not fully understood. Herein, we aimed to investigate the genetic and transcriptomic profiles of sporadic PA. Methods: Whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) of 41 patients with PA and RNA-seq of 5 normal parathyroid tissues were performed. Gene mutations and characterized expression changes were identified. To elucidate the molecular mechanism underlying PA, unsupervised consensus clustering of RNA-seq data was performed. The correlations between the sequencing data and clinicopathological features of these patients were analyzed. Results: Previously reported PA driver gene mutations, such as MEN1 (9/41), mTOR (4/41), ZFX (3/41), CASR (3/41), EZH2 (2/41) and FAT1 (2/41), were also identified in our cohort. Furthermore, somatic mutation of EZH1, which had not been reported in PA, was found in 4 samples. RNA-seq showed that the expression levels of 84 genes were upregulated and 646 were downregulated in PA samples compared with normal samples. Unsupervised clustering analysis of RNA-seq data clustered these patients into 10 subgroups related to mutation or abnormal expression of a group of potential pathogenic genes. Conclusion: MEN1, EZH2, CASR, EZH1, ZFX, mTOR and FAT1 mutations in PA were revealed. According to the RNA-seq data clustering analysis, cyclin D1, ß-catenin, VDR, CASR and GCM2 may be important factors contributing to the PA gene expression profile.


Subject(s)
Adenoma/genetics , Adenoma/metabolism , Exome , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism , Transcriptome , Adult , Aged , Cadherins/genetics , Cadherins/metabolism , Cluster Analysis , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Female , Gene Expression Regulation , Genomics , Humans , Hyperparathyroidism/genetics , Hyperparathyroidism/metabolism , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Male , Middle Aged , Mutation , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , RNA-Seq , Receptors, Calcium-Sensing/genetics , Receptors, Calcium-Sensing/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Tissue Banks
17.
Front Endocrinol (Lausanne) ; 12: 643328, 2021.
Article in English | MEDLINE | ID: mdl-33833736

ABSTRACT

Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.


Subject(s)
Liver Neoplasms/secondary , Lymphatic Metastasis , Parathyroid Hormone/metabolism , Parathyroid Neoplasms/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Calcium/metabolism , Cinacalcet/pharmacology , Disease Progression , Female , Fluorodeoxyglucose F18 , Humans , Immune System , Immunotherapy , Middle Aged , Molecular Biology , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Parathyroid Neoplasms/pathology , Positron Emission Tomography Computed Tomography , Tomography, X-Ray Computed , Treatment Outcome , Ultrasonography
18.
Int J Mol Sci ; 22(4)2021 Feb 18.
Article in English | MEDLINE | ID: mdl-33670622

ABSTRACT

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Parathyroid Glands/metabolism , Parathyroid Neoplasms/genetics , Receptors, Calcium-Sensing/genetics , Transcription Factors/genetics , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Amides/pharmacology , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Gene Expression/drug effects , HEK293 Cells , Humans , Parathyroid Neoplasms/metabolism , Phenethylamines/pharmacology , Propylamines/pharmacology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Pyridines/pharmacology , RNA Interference , Receptors, Calcium-Sensing/agonists , Receptors, Calcium-Sensing/metabolism , Transcription Factors/metabolism , Tumor Cells, Cultured , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , YAP-Signaling Proteins , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/metabolism
19.
Clin Nucl Med ; 46(2): 151-152, 2021 Feb 01.
Article in English | MEDLINE | ID: mdl-33315680

ABSTRACT

ABSTRACT: A 51-year-old man with a palpable neck mass and elevated parathyroid hormone was referred to our department for parathyroid scintigraphy. After injection of 740 MBq 99mTc-MIBI, a dual-phase scan was obtained, which revealed a persistent and intense focal hyperactivity in the left side of the neck (compatible with the neck mass). Thyroid scan with 99mTcO4- also showed increased uptake of the mass, similar to a hot thyroid nodule. After surgery, parathyroid carcinoma was confirmed pathologically. This case demonstrates a rare presentation of parathyroid carcinoma as a hot nodule in thyroid scan, which has been attributed to hypervascularity of the lesion.


Subject(s)
Parathyroid Neoplasms/diagnostic imaging , Parathyroid Neoplasms/metabolism , Sodium Pertechnetate Tc 99m/metabolism , Biological Transport , Female , Humans , Middle Aged , Radionuclide Imaging
20.
Endocr Relat Cancer ; 28(1): 53-63, 2021 01.
Article in English | MEDLINE | ID: mdl-33151903

ABSTRACT

Tumors of the parathyroid glands are highly vascularized and display a microRNA (miRNA) profile divergent from normal parathyroid glands (PaNs). Angiogenic miRNAs, namely miR-126-3p, miR-126-5p, and miR-296-5p, have been found downregulated in parathyroid tumors. Here, we show that miR-126-3p expression levels are reduced in parathyroid adenomas (PAds; n = 12) compared with PaNs (n = 4). In situ hybridization (ISH) of miR-126-3p and miR-296-5p in 10 PAds show that miR-126-3p is expressed by endothelial cells lining the walls of great vessels and by cells within the thin stroma surrounding acinar structures. At variance, miR-296-5p was detectable in most PAd epithelial cells. Combining ISH for miR-126-3p with immunohistochemistry for the endothelial and mesenchymal markers CD34, CD31 and α-smooth muscle actin (αSMA), we could identify that miR-126-3p is localized in the αSMA-positive thin stroma. Further, miR-126-3p-expressing cells are enriched in the CD34-positive stromal cells surrounding epithelial cell acinar structures, a cellular pattern consistent with tumor-associated myofibroblasts (TAMs). In line with this, CD34-positive cells, sorted by FACS from PAds tissues, express miR-126-3p at higher levels than CD34-negative cells, suggesting that miR-126-3p downregulation promotes the endothelial-to-αSMA+ mesenchymal transition. In human mesenchymal stem cells derived from bone marrow (hBM-MSCs), a model of TAMs, the co-culture with PAds-derived cells for 5 days decreases miR-126-3p, while it increases VEGFA expression. At variance, adrenomedullin (ADM) expression is unaffected. Finally, overexpression of the miR-126-3p mimic in both hBM-MSCs and PAds-derived explants downregulates VEGFA expression levels. In conclusion, miR-126-3p is expressed by both endothelial cells and TAMs in PAds, and its downregulation promotes neoangiogenesis, possibly through VEGFA overexpression.


Subject(s)
MicroRNAs/metabolism , Parathyroid Neoplasms/blood supply , Aged , Female , Humans , Male , MicroRNAs/genetics , Middle Aged , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/metabolism
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